It is now no secret that the brain plays a crucial role in organizing, adapting and restraining the systemic inflammatory response via a complex cascade of mechanisms involving proteins of the innate immune system, molecules of the proinflammatory signal transduction pathways, prostaglandins (PGs) and specific populations of neurons. These neuronal circuits, in particular those controlling autonomic functions, are all together involved in engaging the physiological responses that may help eliminating the foreign material and adjust the inflammatory events to prevent detrimental consequences. For instance, elevation in plasma glucocorticoid levels is one of the most powerful endogenous and well-controlled feedback on the pro-inflammatory signal transduction machinery taking place across the organisms. The main Center that controls this neuroendocrine system is the paraventricular nucleus of the hypothalamus (PVN) that receives neuronal projections from numerous hypothalamic and extra-hypothalamic nuclei and areas. There is now compelling evidence that molecules produced by cells of the blood-brain barrier (BBB) may bind to their cognate receptors expressed at the surface of neurons that are responsible to trigger the hypothalamic-pituitary adrenal (HPA) axis. This review presents the new molecular insights regarding the pro-inflammatory signal transduction pathways that occur in these cells and how they are related to the neuroendocrine circuits mediating the increase in plasma glucocorticoid levels during systemic and localized immunogenic insults.